Parathyroid hormone and phosphate homeostasis in patients with Bartter and Gitelman syndrome: an international cross-sectional study

Bartter syndrome; Parathyroid hormone; PhosphateSíndrome de Bartter; Hormona paratiroidea; FosfatoSíndrome de Bartter; Hormona paratiroïdal; FosfatBackground Small cohort studies have reported high parathyroid hormone (PTH) levels in patients with Bartter syndrome and lower serum phosphate levels have anecdotally been reported in patients with Gitelman syndrome. In this cross-sectional study, we assessed PTH and phosphate homeostasis in a large cohort of patients with salt-losing tubulopathies. Methods Clinical and laboratory data of 589 patients with Bartter and Gitelman syndrome were provided by members of the European Rare Kidney Diseases Reference Network (ERKNet) and the European Society for Paediatric Nephrology (ESPN). Results A total of 285 patients with Bartter syndrome and 304 patients with Gitelman syndrome were included for analysis. Patients with Bartter syndrome type I and II had the highest median PTH level (7.5 pmol/L) and 56% had hyperparathyroidism (PTH >7.0 pmol/L). Serum calcium was slightly lower in Bartter syndrome type I and II patients with hyperparathyroidism (2.42 versus 2.49 mmol/L; P = .038) compared to those with normal PTH levels and correlated inversely with PTH (rs −0.253; P = .009). Serum phosphate and urinary phosphate excretion did not correlate with PTH. Overall, 22% of patients had low serum phosphate levels (phosphate—standard deviation score < −2), with the highest prevalence in patients with Bartter syndrome type III (32%). Serum phosphate correlated with tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) (rs 0.699; P < .001), suggesting renal phosphate wasting. Conclusions Hyperparathyroidism is frequent in patients with Bartter syndrome type I and II. Low serum phosphate is observed in a significant number of patients with Bartter and Gitelman syndrome and appears associated with renal phosphate wasting.This project has been supported by the European Reference Network for Rare Kidney Diseases (ERKNet), which is partly co-funded by the European Union within the framework of the Third Health Programme ‘ERN-2016-Framework Partnership Agreement 2017–2021’. This work is generated within the European Society for Paediatric Nephrology working group on inherited renal disorders. This work was supported by an Innovation Grant 19OI06 from the Dutch Kidney Foundation (to T.N.)

Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA

Background: Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl− cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. Methods: We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. Results: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF), and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. Conclusion: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies

Genome-wide Meta-analysis Unravels Novel Interactions between Magnesium Homeostasis and Metabolic Phenotypes

Magnesium (Mg &lt;sup&gt;2+&lt;/sup&gt; ) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg &lt;sup&gt;2+&lt;/sup&gt; , which is crucial for Mg &lt;sup&gt;2+&lt;/sup&gt; homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg &lt;sup&gt;2+&lt;/sup&gt; homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (P=4.4×10 &lt;sup&gt;-13&lt;/sup&gt; ) near TRPM6, which encodes an epithelial Mg &lt;sup&gt;2+&lt;/sup&gt; channel, and rs35929 (P=2.1×10 &lt;sup&gt;-11&lt;/sup&gt; ), a variant of ARL15, which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg &lt;sup&gt;2+&lt;/sup&gt; regulated the expression of the highly conserved ARL15 ortholog arl15b, and arl15b knockdown resulted in renal Mg &lt;sup&gt;2+&lt;/sup&gt; wasting and metabolic disturbances. Finally, ARL15 rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene-environment interaction linking Mg &lt;sup&gt;2+&lt;/sup&gt; deficiency to insulin resistance and obesity

Pathophysiological aspects of the thick ascending limb and novel genetic defects: HELIX syndrome and transient antenatal Bartter syndrome

International audienceThe thick ascending limb plays a central role in human kidney physiology, participating in sodium reabsorption, urine concentrating mechanisms, calcium and magnesium homeostasis, bicarbonate and ammonium homeostasis, and uromodulin synthesis. This review aims to illustrate the importance of these roles from a pathophysiological point of view by describing the interactions of the key proteins of this segment and by discussing how recently identified and long-known hereditary diseases affect this segment. The descriptions of two recently described salt-losing tubulopathies, transient antenatal Bartter syndrome and HELIX syndrome, which are caused by mutations in MAGED2 and CLDN10 genes, respectively, highlight the role of new players in the modulation of sodium reabsorption the thick ascending limb

Syndrome de Bartter néonatal, corrélation phénotype génotype (à partir d'une cohorte de 34 patients)

Le syndrome de Bartter néonatal (BS) est une tubulopathie héréditaire due à des mutations de gènes codant pour des molécules participant à la réabsorption du sel dans le néphron distal : SLC12A1 (BS type I), KCNJ1 (BS type II), CLCNKB (BS type III) ou BSND (BS type IV). 34 enfants présentant un BS génétiquement confirmé ont été suivis avec un recul moyen de 7,4 ans. Le BS de type II est le plus fréquent avec une hyperkaliémie initiale notée chez 61% des enfants. A l inverse, l'hypokaliémie est constante et profonde dans les BS de type III. Un hydramnios, une prématurité et une polyurie caractérisent les BS de type I, II et IV alors que l'expression clinique des patients porteurs de mutations du gène CLCNKB est variable, soit une forme anténatale soit une forme proche d'un BS classique. Sous supplémentation hydroélectrolytique et indométacine, la majorité des enfants ont un rattrapage staturo-pondéral. L'évolution vers l'insuffisance rénale est rare et probablement multifactorielle.TOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Syndrome d'hypomagnésémie, hypercalciurie, néphrocalcinose familiale (histoire naturelle et corrélation phénotype génotype chez 22 patients porteurs de mutations des gènes CLDN16 ou CLDN19)

BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Les grandes avancées en néphro-génétique pédiatrique

L’essor de la génétique au cours des dernières décennies a permis des avancées majeures dans la compréhension des mécanismes conduisant aux maladies rénales héréditaires. Des premières études par clonage positionnel jusqu’à l’avènement du séquençage à haut débit (NGS), les techniques d’analyse du génome sont devenues de plus en plus performantes, avec un niveau de résolution extraordinaire. Les prix de séquençage se sont effondrés, passant d’un million de dollars (environ 940 millions d’euros) pour le séquençage du génome de James Watson en 2008, à quelques centaines d’euros pour le séquençage d’un génome aujourd’hui. Le diagnostic moléculaire tient ainsi une place centrale pour le diagnostic des patients et influe sur la prise en charge thérapeutique dans de nombreuses situations. Mais si le NGS est un outil performant pour l’identification de variants impliqués dans les maladies, il expose au risque de surinterprétation de certains variants, conduisant à des diagnostics erronés. Dans cette revue, nous proposons une brève rétrospective des étapes essentielles qui ont conduit aux connaissances actuelles et au développement du NGS pour l’étude des néphropathies héréditaires de l’enfant. Nous développerons ensuite les principales néphropathies héréditaires et les mécanismes moléculaires sous-jacents

Recurrent Nephrolithiasis in a Patient With Hypercalcemia and Normal to Mildly Elevated Parathyroid Hormone

A 42-year-old man was referred to our stone clinic for recurrent episodes of symptomatic nephrolithiasis. Spontaneous stone passages occurred at the ages of 25, 40, and 42 years with one need for endoscopic stone removal. Calculi were composed of 100% calcium oxalate monohydrate. The patient had not taken any medication or supplements. Increased fluid intake was the only intervention for stone prevention. Metabolic work-up at presentation revealed mild hypercalcemia and normal to mildly elevated intact parathyroid hormone, even after repletion with oral 25-hydroxyvitamin D. 1,25-Dihydroxyvitamin D level and 24-hour urinary calcium excretion were within normal ranges (Table 1). Physical examination was unremarkable. Family history was negative for nephrolithiasis or hypercalcemia. • What are the main differential diagnoses of hypercalcemia with an elevated PTH level in this patient? • What tests help to distinguish between these two entities? • Which additional studies help to verify the diagnosis

How Bartter’s and Gitelman’s Syndromes, and Dent’s Disease Have Provided Important Insights into the Function of Three Renal Chloride Channels: ClC-Ka/b and ClC-5

International audienceChloride channels are expressed in almost all cell membranes and are potentially involved in a wide variety of functions. The kidney expresses 8 of the 9 chloride channels of the ClC family that have been cloned so far to date in mammals. This review focuses on the pathophysiology of two renal disorders that have contributed recently to our understanding of the physiological role of chloride channels belonging to the ClC family. First are the related syndromes of Bartter's and Gitelman's, in which inactivating mutations of the genes encoding either of the ClC-Ks, or their regulatory beta-subunit barttin, have shown the important contribution of these chloride channels to renal tubular sodium and chloride (NaCl) transport along the loop of Henle and distal tubule. Second is the renal Fanconi syndrome known as Dent's disease, in which ClC-5 disruption has revealed the key role of this endosomal chloride channel in the megalin-mediated endocytotic pathway in the proximal tubule. The underlying pathophysiology of this inherited disorder demonstrates how ClC-5 is directly or indirectly required for the reabsorption of filtered low-molecular-weight proteins and bioactive peptides, also expression of membrane transporters, and clearance of calcium-based stone-forming crystals

QT Interval in Adult with Chronic Hypokalemia due to Gitelman Syndrome

International audienc